Neuroinflammation from ultrasound-driven blood-brain barrier modulation features early NFκB innate and late interferon immune stages

Abstract Focused ultrasound with microbubbles noninvasively and transiently modulates the blood-brain barrier (BBB), enabling precise transvascular solute transport. This procedure minimizes edema and hemorrhage while avoiding long-term physiological and cognitive effects. Currently, this is in clinical trials for Alzheimer’s disease and brain cancers. As with any neurovascular insult, treatment may elicit a sterile inflammatory response (SIR), scaling with increasing mechanical index and microbubble dose. Most studies employ moderate parameters that induce Class II SIR with robust BBB modulation, with reports indicating acute immune activation within 5 min and up to 3 days post-treatment; however, longer-term dynamics remain unclear. Thus, we profiled murine brain transcriptomics for a week post-treatment. Integrative analyses identified a biphasic inflammatory response, characterized by an initial NFκB-driven peak at 3–6 h, followed by an interferon-mediated phase at 48 h that attenuates by a week. This finding reconciles prior inconsistencies, providing insights into establishing therapeutic windows and enhancing neuroinflammatory modulation strategies.